Heart failure (HF) is a major medical problem in the United States affecting more than 5 million patients. It is expected to impact 11 million patients by 2011. Of these patients, over 40% have a defect in the ability of the heart muscle to relax which prevents the heart from filling with blood normally (diastolic dysfunction). While there are several therapies and AHA/ACC consensus guidelines for the treatment of (systolic) abnormalities, there are no guidelines and few therapies exist for the treatment of diastolic dysfunction, a large unmet medical need. The novel and innovative solution to this problem provided by Phrixus is the biological membrane sealant Poloxamer-188 (P- 188) with a chronic treatment market potential in the billions of dollars. In studies published in Nature in 2005, Dr. Metzger and colleagues provided evidence that, in a muscular dystrophy model of HF, P-188 is able to act as a molecular band-aid, plugging microscopic tears in the membrane of cardiac muscle cells, preventing abnormal entry of extracellular calcium, a stimulator of muscle contraction, into the cells. Thus cells can maintain near normal calcium levels resulting in better relaxation and less diastolic dysfunction. Phrixus is currently working toward an investigative new drug application with the FDA and plans to have P-188 in the clinic in late 2007. P-188 has been in Phase III clinical trials for other indications and has been shown to be safe in an acute dosing regiment in over 4000 patients. This proposal will provide the first evidence that P-188 will be effective in prolonged treatment of ischemic HF and provide evidence to support its mechanism of action. This evidence will be necessary to recruit clinical investigators and convince cardiologists to enroll their patients in clinical trials. A 16-week study in the rat myocardial infarction (MI) model of HF will be run. Groups of animals will be sacrificed at 4 week intervals and examined for changes in the levels of membrane dystrophin, the presence ands extent of sarcolemma leakage, for levels of muscle cell damage markers in their serum, and the ability of P-188 treatment to reverse these affects with 4 weeks of treatment from week 13-16. At 16 weeks, parameters of systolic and diastolic heart function will be measured in P-188 treated and untreated MI and sham rats to confirm that prolonged treatment is functionally beneficial. In a phase II proposal, Phrixus will request funding for development of P-188 as a chronic HF therapy including long-term safety and efficacy studies. [unreadable] [unreadable] [unreadable]